This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human p97 is a AAA protein which hydrolyze ATP to drive the mechanical works. Structurally, there are three domains in p97, an N-domain followed by two AAA ATPase domains, D1 and D2. The N-domain is responsible for interacting with adaptor proteins and is essential for polyubiquitin binding. The D2-domain exhibits the major ATPase activity while D1-domain only shows a very weak ATPase activity. Crystal structures of both full-length and truncated p97-ND1 were solved. In all of them, the N-domain shows a single conformation and the D1-domain always bound with ADP regardless the forms of nucleotide added. Specific mutations in p97 have been tied to IBMPFD patients with the observation of accumulation of aggregated, polyubiquitinated proteins muscle cells. All mutations were mapped exclusively to the N- and D1-domain. Interestingly, these mutants are able to form hexamers and display similar ATPase activity to the wild type in vitro. Together with the knowledge that N-domain alone is capable of interacting with polyubiquitin, truncated p97-ND1 is used in the present study as a model system to investigate potential structural changes for mutations that causes the protein become functionally defective. We have solved the crystal structure of several disease-associated p97-ND1 and interestingly, all of them show a different N-domain conformation which has not been reported previously. In addition, the D1-domains of all mutant p97 are bound with ATPgammaS which is different from the wild type where ADP is always found. More importantly, this conformational change is reversible when substituting ATPgS with ADP. This strongly suggests an induced conformational change of p97 by different types of bound nucleotides. To extend our findings to the full-length p97, we would like to have some hints if this conformational change can also be observed in full-length p97. By adding different nucleotides, we hope to observe changes in X-ray scattering in the proposed SAXS experiment.